Cancer is typically treated with either chemotherapy and/or radiation therapy. While this type of ablation therapy is often effective to destroy a significant amount of tumor cells, such therapies often leave behind a number of tumor cells that are resistant to the treatment. These resistant cells can proliferate and/or metastasize to form new tumors that are also recalcitrant to treatment. Furthermore, the use of known combinations of chemotherapeutic drugs has given rise to multidrug resistant (‘MDR’) tumor cells.
The American Cancer Society estimates there will be more” than 15,000 new cases and more than 4,500 deaths from chronic lymphocytic leukemia (CLL) in 2013 alone. This condition is characterized by the accumulation of mature CD5+CD19+CD23+ B lymphocytes in peripheral blood, hone marrow, lymph nodes and spleen, which is thought to be caused by a defect in the pathway to regulated cell death rather than an uncontrolled mechanism of cell proliferation. Such defect can lead to chemoresistance and thus strategies aimed to correct it can serve as additional therapies to traditional chemotherapy or lead to more potent therapeutics. The B-cell lymphoma/leukemia 2 (BCL-2) protein is over-expressed in CLL and therefore represents a target in attempts to overcome the resistance of tumors to anti-cancer treatments. CLL is a debilitating leukemia and hence there is an urgent need for selective treatments for this disease.
Microtubules are filamentous polymers that are key components of the lymphocytic cell cytoskeleton. They are dynamic structures fluctuating between states of polymerisation and depolymerization. This property enables microtubules to modulate cell shape, adhesion, migration and proliferation. Compounds that act as tubulin polymerisation inhibitors (TPI's) directly disrupt microtubule polymerisation processes and consequently have the ability to effect cell shape changes and inhibit cell proliferation. These properties are central to the use of TPI's as therapeutics for the treatment of cancer and in the combinations of the present invention.
TPI compounds are important in the treatment of cancers primarily as a result of their capacity to selectively shut down blood flow through a tumor. Targeting tubulin polymerization inhibition has been a very well validated anti-cancer approach through the development and now extensive clinical use of chemotherapeutic TPI's agents.
TPI's can be classified based on their specific tubulin binding site.
Binding of vinca alkaloids to tubulin defines a site that mediates the tubulin destabilization activity seen with these compounds. The ‘vinca’ site has been shown to directly bind a number of compounds that effect destabilization of tubulin.
Colchicine binding to tubulin defines an independent binding site that like in the case of the ‘vinca’ site causes destabilization of tubulin. Although TPI's binding to the ‘vinca’ sites has been exploited in their use as anti-cancer chemotherapeutics, ‘colchicine’ site binders have been in comparison neglected, possibly due to the lack of therapeutic margins offered by colchicine. However, more recently a number of ‘colchicine’ site binding agents have been described that have the ability to cause disruption of blood vessels within solid tumors. These TPI's are referred to as Vascular Disruption Agents (VDA). Many of the ‘colchicine’ site binding agents that exhibit VDA capability are based on natural products such as combretastatins (CA4P, OXi-4503, AVE-8062), colchicines (ZD6126) and phenylahistin (NPI-2358) while others are synthetic compounds (MN-029 and EPC2407).
TPIs act as VDAs because they interfere with microtubule integrity, leading to cytoskeletal changes of the endothelial cells that line the blood vessels of the tumor. As a result, these usually flat cells become more rounded, and lose their cell to cell contact. These events lead to narrowing of tumor blood vessels and ultimately occlusion of blood flow through the vessels. The tumor selectivity associated with these agents results from the fact that tumor vasculature is weaker and more prone to collapse than normal vasculature. Nonetheless, a number of the dose limiting toxicities associated with VDAs are due to a reduction in blood flow in healthy tissues.
There is a need for a more efficacious and selective treatment of CLL.